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Published on: February 22, 2015
Genome scale CRISPR Cas9a knockout screen reveals genes that control glioblastoma susceptibility to the alkylating
Chidiebere U Awah1,2, Jan Winter3, Olorunseun O Ogunwobi1,2,4
1Department of Biological Sciences, Hunter College of The City University of New York, New York, NY, USA.
Abstract:
Glioblastoma is the most fatal of all primary human brain tumors with 14 months median survival. The mainstay therapy for this tumor involves temozolomide, surgery, radiotherapy and tumor treating electric field. Cancer resistance to commonly available chemotherapeutics remains a major challenge in glioblastoma patients receiving treatment and unfavorably impact their overall survival and outcome. However, the lack of progress in this area could be attributed to lack of tools to probe unbiasedly at the genome wide level the coding and non-coding elements contribution on a large scale for factors that control resistance to chemotherapeutics. Understanding the mechanisms of resistance to chemotherapeutics will enable precision medicine in the treatment of cancer patients. CRISPR Cas9a has emerged as a functional genomics tool to study at genome level the factors that control cancer resistance to drugs. Recently, we used genome wide CRISPR-Cas9a screen to identify genes responsible for glioblastoma susceptibility to etoposide. We extended our inquiry to understand genes that control glioblastoma response to temozolomide by using genome scale CRISPR. This study shows that the unbiased genome-wide loss of function approach can be applied to discover genes that influence tumor resistance to chemotherapeutics and contribute to chemoresistance in glioblastoma.
Insights
This study used genome-wide CRISPR screens to identify genes influencing glioblastoma (a fatal brain tumor) resistance to chemotherapy. Unbiased functional genomics approaches can uncover novel targets for improving patient outcomes and enabling precision medicine.
Area of Science:
- Neuro-oncology
- Cancer Genomics
- Functional Genomics
Background:
- Glioblastoma is a highly fatal brain tumor with poor prognosis.
- Current therapies, including temozolomide, often face challenges due to cancer chemoresistance.
- Understanding chemoresistance mechanisms is crucial for advancing precision medicine in glioblastoma treatment.
Purpose of the Study:
- To identify genes that control glioblastoma's response to temozolomide using a genome-wide approach.
- To leverage functional genomics tools for discovering factors contributing to cancer drug resistance.
- To enable the development of novel therapeutic strategies for glioblastoma.
Main Methods:
- Utilized genome-wide CRISPR-Cas9 loss-of-function screens.
- Applied these screens to glioblastoma models to assess drug response.
- Focused on identifying genes influencing resistance to temozolomide.
Main Results:
- Demonstrated the utility of unbiased, genome-wide loss-of-function screens in discovering chemoresistance genes.
- Identified specific genes that modulate glioblastoma's sensitivity to temozolomide.
- Provided insights into the genetic underpinnings of glioblastoma chemoresistance.
Conclusions:
- Unbiased genome-wide CRISPR screens are effective tools for identifying genes involved in glioblastoma chemoresistance.
- This approach can uncover novel therapeutic targets to overcome drug resistance.
- Findings contribute to advancing precision medicine for glioblastoma patients.
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